Interleukin-6 (IL-6) is a cytokine secreted by many cell types, including skeletal muscle. Under basal conditions, skeletal muscle IL-6 expression is minimal, but its mRNA expression and secretion increase up to a hundredfold in response to a single bout of endurance exercise. Secreted IL-6 appears to act as a sensor linking increased muscle activity with mobilization of substrate stores from liver and fat, as it increases liver glycogenolysis and adipose lipolysis. Currently the molecular mechanisms governing exercise-induced IL-6 expression in skeletal muscle are poorly defined. The purpose of this proposal is to develop an integrative, translational program of research using animal models and human studies to elucidate the mechanisms underlying exercise-induced IL-6 expression in skeletal muscle. The major aims of this research are threefold: (1) to develop a mouse model of IL-6 exercise responsiveness with which we will test the effects of different exercise paradigms on IL-6 expression in vivo;(2) to examine whether increased transcription is responsible for the increase in IL-6 mRNA expression in mouse and human muscle in response to exercise;(3) to determine whether specific IL-6 promoter polymorphisms affect muscle IL-6 expression in human subjects undergoing a single bout of endurance exercise. IL-6 pre-mRNA, mature IL-6 mRNA, and luciferase activity will be quantified in response to a single bout of endurance exercise in mice containing an IL-6 promoter- reporter transgene. In addition, we will compare the effects of different exercise modalities (voluntary vs. forced running), different exercise variables (intensity and duration), and muscle fiber type on the exercise IL-6 response. Finally, human subjects will be genotyped for the IL-6 -174 G/C polymorphism and will be exercised to determine whether exercise-induced IL-6 transcription differs in subjects with different IL-6 genotypes. Together these data should provide insights into the mechanisms governing exercise-induced IL-6 expression in muscle that may assist in the development of optimally effective training programs for persons suffering from conditions such as obesity and diabetes which are characterized by defects in substrate mobilization. The proposed research seeks to understand how a gene called interleukin-6 (IL-6) is regulated in skeletal muscle in response to exercise. IL-6 released by skeletal muscle during exercise signals the fat and the liver to release their stores of sugars and fats for use by the contracting muscle, and thus understanding how IL-6 is regulated, and how this gene is turned on during exercise, may provide insights into how to design better exercise regimens to optimize fat and sugar utilization during exercise. This in turn may help prevent the development of disorders such as obesity and diabetes, and may help people who already have these conditions to improve their metabolism and reduce the negative effects of these conditions on their health and well-being.